Clinical, biological and endoscopic indices are commonly used to identify patients at high risk for a severe disease course. Ideally, an instrument useful to measure activity of IBD should be reproducible, valid, responsive to change of the disease course, easy to administer and based on accepted standard of reporting. Multi-item measurements of disease activity have been developed in order to allow uniformity between observers when assessing patients and stratifying them into groups with different degrees of disease activity.

In Crohn disease (CD), the most commonly used instruments to measure activity are the activity index (CDAI) [7], that is a widely accepted tool for adult trials, and the pediatric CD activity index (PCDAI), approved and widely used in children (Table 42.2) [8]. In comparison with the CDAI, the PCDAI decreases the emphasis on subjective items while taking into account height velocity and adding laboratory parameters such as erythrocyte sedimentation rate and serum albumin level. Despite the inclusion of a variable such as linear growth that would not be expected to change during an interval of a few weeks, the PCDAI has been demonstrated to be responsive to changes in disease activity over a time interval such as that of an acute treatment trial [9]. In the original multicenter validation study of PCDAI, it was shown that a PCDAI cut score of ≤10 was able to classify “correctly” 69 % of patients based on physician global assessment (PGA) of inactive vs. active disease [8]. Then, the clinimetric properties of the PCDAI (including validity, reliability, and responsiveness) have been evaluated in four studies [9–12]. Three of those [9–11] determined cut scores for remission based on PGA, but with heterogeneous results (<  10  –  <  15 points). Recently, on the basis of a large study aiming at addressing the discrepancies in published cutoff values used to define remission and response [12] cutoff values were <10 points for remission, 10–27.5 for mild disease, 30–37.5 for moderate disease, and 40–100 for severe disease. A cutoff of >12.5 points was suggested to be used as response criteria, and identified as the “minimally important difference” (MID) that corresponds to a change of at least one category on the PGA between two visits. Pediatric clinical trials should also include the evaluation of linear growth, that is widely accepted as a marker of the adequacy of control of intestinal inflammation [10]; indeed, persistence of delay in longitudinal growth is commonly thought to be a sensitive marker of underlying active inflammatory process in the gut [13]. Despite that height velocity is commonly considered as the most sensitive traditional variable to measure growth pattern, there are problems in the interpretation of height velocity data: reproducible serial measurements of the height are essential with a well calibrated wall mounted stadiometer; height velocity should be calculated over intervals of no less than 6 months and must be evaluated in the context of maturity, gender, and age; height velocity should be converted to a standard deviation score (Z score) for height velocity according to chronological age if maturity is normal, or according to bone age if maturity is delayed or advanced. Cross-sectional studies have shown a good correlation between markers of bone and collagen turnover that reflect the childhood growth curve [14]; however, due to the “pulse” (not linear) nature of the normal growth, collagen metabolism measurements at a single point in time do not necessarily reflect growth pattern over a follow up period of 6–12 months in a clinical trial or a cohort study. In general, when growth pattern is considered in pediatric IBD, it is recommended that height velocity is included in therapeutic trials of IBD children with a duration of 6 months or longer (as it occurs in the maintenance remission trials or in the prevention of postoperative recurrence trials); adolescents in the post-pubertal phase can be excluded from this aspect of outcome evaluation. In order to compare children with different ages and stages of pubertal development, the measured height velocity should be given as the Z score; finally, height velocity should not be considered in acute disease treatment trials, but a post-study follow up height velocity calculation (i.e., every 6 months) should be accomplished. Clinical disease activity indices do not include the use of corticosteroids as outcome. Steroids are commonly used during disease flare-ups, but due to significant morbidity with long-term use, they should not be used for mainteinance of remission. Several trials have incorporated an additional end-point of corticosteroid-free remission and pediatric trials should also include this significant outcome.

Clinical indices of IBD are somewhat subjective and correlate poorly with endoscopic inflammation that can continue despite the absence of clinical features. The presence of chronic inflammatory lesions of the intestinal mucosa causes not only classic gastrointestinal symptoms such as diarrhea, pain, and poor health status but also nutritional burdens. Mucosal ulcerations may cause loss of proteins, electrolytes, fluid, and iron; furthermore, important systemic and extraintestinal complications, such as growth failure or arthropathy, are due to the delivery of pro-inflammatory cytokines from the inflamed tissue [15]. Thus, treatment of IBD should be aimed both at relieving symptoms and at healing mucosal lesions, in an attempt to restore an adequate nutritional status and minimize systemic effects of the disease [16].

Mucosal disease severity is commonly defined by the CD Endoscopic Index of Severity (CDEIS), developed and validated for evaluating mucosal healing [17]. The CDEIS includes assessment in five separate segments from ileum to rectum (ileum, right colon, transverse colon, left colon and rectum), the number of deep ulcerations, the number of superficial ulcerations, segmental surfaces involved with disease per 10 cm and segmental ulcerated surface per 10 cm. In addition, the presence of stenosis is included in the score. Total score range from 0 to 44. A cutoff has not yet been defined for endoscopic remission, although higher scores are indicative of more severe disease.

In 2004 a simplified version of CDEIS has been developed: the Simplified Endoscopic Activity Score for CD (SES-CD) [18]. This score has four variables: ulcer size, ulcerated surface, extent of affected surface and presence and type of narrowing. A numerical score of 0–3 is given to each segment of the colon and the sum of the variables provides a grading of the severity of the disease. SES-CD is simple and easy to be used in comparison to CDEIS. This is particularly significant, as endoscopic remission has become important in assessing the efficacy of treatment for CD in clinical trials.

In contrast to CD and until recently, no single multi-attribute measure has been consistently employed in either adult or pediatric ulcerative colitis (UC). Heterogeneous outcome measures have been used in adults with UC and also employed in pediatric clinical trials (Mayo Clinic Score, Sutherland, Rachmilewitz). These determined several general issues, because they were generally non-specific, sometimes not prospecitvely validated, finally the scores of the indices were typically derived by incorporating various signs and symptoms for which there are no standardized definitions. In 2007 a pediatric UC activity index (PUCAI) was developed and validated using prospectively enrolled cohorts of children with UC [19]. PUCAI, lacking invasive tests, includes several clinical and laboratory items such as stool number, consistency and blood, abdominal pain, activity level, nocturnal diarrhea, serum albumin and CRP (Table 42.3). The cutoff to differentiate remission from active disease was <10 points (sensitivity 89 %, specificity 89 %), to differentiate mild from moderate disease activity at least 30 points (sensitivity 95 %, specificity 95 %), and moderate disease activity from severe at least 65 points (sensitivity 92 %, specificity 94 %), with a MID at 20 points [20]. PUCAI is suitable for longitudinal use in clinical trials and for determining timely introduction of second-line therapy in severe acute UC [21]. Other scores were based on increased emphasis on endoscopic features: Rachmilewitz developed an endoscopic index, scoring for granularity, vascular pattern, vulnerability and mucosal damage [22]. This score is numerical and has been used in adult clinical trials. The Baron scale, distinguishing three grades of activity, is the most commonly used score to assess the degree of endoscopic activity [23]. To combine the advantages of the clinical Truelove score and the endoscopic Baron scale, the Mayo score has been developed and is currently the favorite score in clinical studies in adults [24].